This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Erythropoetin (EPO) has recently been discovered to play an important role in protection of the brain against hypoxia, in a variety of in vitro and amimal models, up to and including primates, reducing neuronal death by 50-70% in these models. These effects occur whether EPO is given before, during, or even a few hours after the hypoxic insult. Thus EPO holds promise as a clinicalneuroprotectant agent;however to date there are no published clinical studies in pediatric patients using EPO in this role. We have demonstrated a significant incidence of cerebral hypoxia in the perioperative period for neonatal cardiac surgery with bypass, using near-infrared spectroscopy (NIRS) to measure brain oxyhemoglobin saturation. Long term neurodevelopmental impairment is reported in 21%-69% of children undergoing cardiac surgery as newborns or young infants in the past 20 years. This prospective, placebo-controlled, double blind, randomized trial of high dose EPO neuroprotection for neonatal cardiac surgery with hypothermic cardiopulmonary bypass, will test the hypothesis that EPO will reduce brain injury in this setting and improve short and long term neurodevelopmental outcomes. This protocol is a novel, translational, interdisciplinary approach consistent with the NIH mission to foster creative research strategies which will potentially improve health outcomes of a significant patient population. The neonatal cardiac surgery model represents the ideal clinical setting for an EPO neuroprotection trial because of the predictable timing and occurrence of cerebral hypoxemia, and the known incidence of later abnormal neurodevelopmental outcomes. If successful, this approach could be tested in a variety of pediatric clinical settings where neurological outcomes are at risk:cardiac surgeryin older patients, perinatal asphyxia, post cardiac arrest, and in neurological trauma and stroke. We will randomize newborns scheduled for cardiac surgery for the arterial switch operation, Norwood Stage I palliation, or aortic arch reconstruction. Each patient will undergo NIRS monitoring pre-, intra- and postoperatively for a total of 96 hours;pre- and postoperative EEg monitoring during the same period;and a brain MRI immediately prior to surgery, and 7 days after surgery. Patients will be randomized to receive EPO, 1000 units/kg per dose IV, or placebo, administered 12-24 hours before surgery, the day of surgery, and the day after surgery. patients will also have had a third brain MRI at 3-6 months;and a complete neurodevelopmental assessment at age 1,3, and 5 yars. The early primary outcome variable will be MRI severity of injury score, and later primary outcome will be Bayley Scales of Infant Development scores.